Chaste Tree

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Vitex agnus-castus L.

[Fam. Verbenaceae]

Overview

Chaste tree, sometimes called chaste berry or vitex, derived its common name from the traditional belief that the plant promoted chastity (Winterhoff, 1998; Christie and Walker, 1997). The fruit of Vitex agnus-castus (hereafter referred to as chaste tree) was used in ancient Greece and Rome by males and females, including the monks of the Middle Ages (as a “functional” food flavoring), to suppress sexual desire (Winterhoff, 1998; Upton, 2001). Chaste tree is a widely used and popular treatment for gynecological disorders, including corpus luteum insufficiency (Merz et al., 1996; Milewicz et al., 1993); premenstrual syndrome (PMS) (Schellenberg et al., 2001, Loch et al., 2000; Dittmar and Böhnert, 1992; Coeugniet et al., 1986; Wuttke et al., 1995); menstrual problems (Loch et al., 1991; Loch and Kaiser, 1990); and cyclic mastalgia (Halaska et al., 1998; Kress and Thanner, 1981; Kubista et al., 1983). It has also been used to treat hormonally induced acne (Amann, 1967). Chaste tree has been traditionally used to treat fibroid cysts and infertility, to stop miscarriages caused by progesterone insufficiency, to flush out the placenta after birth (McGuffin et al., 1997; Peirce, 1999), and as a digestive aid, sedative, and anti-infective (Christie and Walker, 1997). Although chaste tree is widely used in Germany, it has not been used in the U.S. much until relatively recently. It has not yet achieved significant popularity in mainstream retail outlets but ranked 54th in natural food store sales in 2001 (Richman and Witkowski, 2001).

Description

Chaste tree is the ripe, dried fruit of Vitex agnus-castus L. [Fam. Verbenaceae], containing no less than 0.4% (v/w) of volatile oil (GHP, 1993), and no less than 8% water-soluble extractive (BHP, 1996). The average water- and ethanol-soluble extractive content is approximately 10% (Abel, 1999). It is unknown which constituents are responsible for chaste tree’s activity, and up to this point there are no official published guidelines for the standardization of chaste tree preparations (Meier, 1999). However, two compounds are presently used as marker compounds for quality control: the iridoid glycoside agnuside and the flavonol casticin (Abel, 1999). Most chaste tree preparations used in European medicine are nonstandardized fluid extracts, tinctures, and/or native dry extracts. The “native” or “total” extract has an approximate 10:1 (w/w) drug-to-extract ratio containing 0.6 –1.0% casticin (Abel, 1999; Morant and Ruppanner, 2001). It has been suggested in the future, pharmaceutical-grade chaste tree preparations should be characterized qualitatively and quantitatively, based on hydrophilic flavonoids, lipophilic compounds, and iridoid glycosides (Hoberg et al., 1999; Upton, 2001).

Primary Uses

Gynecology

Dysmenorrhea (Bubenzer, 1993; Loch et al., 1991; Loch and Kaiser, 1990; Bleier, 1959; Probst and Roth, 1954)

Hyperprolactinemia and corpus luteum insufficiency (Merz et al., 1996; Milewicz et al., 1993; Propping et al., 1991; Propping and Katzorke, 1987)

Premenstrual syndrome (PMS) (Schellenberg et al., 2001; Loch et al., 2000; Berger et al, 2000; Berger et al., 1999; Lauritzen et al., 1997; Turner and Mills, 1993; Dittmar and Böhnert, 1992; Coeugniet et al., 1986)

Note: The German Commission E recommended that women who experience tension or swelling of the breasts, or menstrual disturbances should consult a healthcare provider for proper diagnosis (Blumenthal, et al., 1998)

Other Potential Uses

Dermatology

Acne vulgaris (Giss and Rothenburg, 1968; Amann, 1967; Bleier, 1959)

Gynecology

Prevention of miscarriage in the first trimester of pregnancy in cases of progesterone insufficiency (McGuffin et al., 1997)

Mastodynia (Halaske et al., 1999; Blumenthal et al., 1998; Kubista et al., 1986)

Insufficient lactation (Bruckner, 1989)

Dosage

Internal

The German Commission E recommended the following daily dosage: Aqueous-alcoholic extract (50–70% v/v), corresponding to 30–40 mg dried fruit (Blumenthal et al., 1998).

Dry native extract [2.6–4.2 mg, depending on concentration ratio, standardized to contain approximately 0.6–1.0% casticin]: 1 tablet swallowed with some liquid each morning (Abel, 1999; Bionorica, 1998; Lauritzen et al., 1997; Madaus, 1996).
Note: Some products (Zeller PreMens^® Ze440) recommend up to 20 mg native extract daily (Morant and Ruppanner, 2001; Berger et al., 1999).

Fluid extract [1:1 (g/ml), 70% alcohol (v/v)]: 0.5–1.0 ml (Karnick, 1994).

Fluid extract [1:2 (g/ml)]: 1.2–4.0 ml (Bone, 1989).

Tincture [Alcohol 58% volume, 100 g of aqueous-alcoholic solution contains 9 g of 1:5 tincture]: 40 drops, once daily with some liquid each morning (Madaus, 1996).

Duration of Administration

Chaste tree does not have an immediate effect. For treatment of PMS, a minimum treatment duration of three months is recommended (Morant and Ruppanner, 2001). A survey of medical herbalists in the U.K. reported a mean average of 4.8 months of treatment is necessary before patients with PMS symptoms respond to chaste tree (Christie and Walker, 1997). For anovulation and infertility, a treatment duration of five to seven months may be necessary. For amenorrhea lasting longer than two years, a treatment period of up to 18 months may be required (Pizzorno and Murray, 1999; Boon and Smith, 1999; Brown, 1994). For most other conditions, symptoms usually start to diminish within one to two months. After four to six months, extensive or complete relief from symptoms may be seen (Pizzorno and Murray, 1999; Brown, 1994).

Chemistry

Mature chaste tree fruit yields 0.4–0.7% (% v/w) essential oil, depending on distillation time and size of comminuted particles (Sørensen and Katsiotis, 2000), and is composed mainly of bornyl acetate, 1,8-cineole, limonene, a- and b-pinene, b-caryophyllene, and a-terpinyl acetate (Meier and Hoberg, 1999). It also contains labdane diterpenoids: 0.04–0.3% rotundifuran, 0.04–0.17% vitexilactone, 0.02–0.1% 6b, 7b-diacetoxy-13-hydroxy-labda-8,14-diene (Hoberg et al., 1999); flavonoids: 0.10–0.16% casticin (Abel, 1999); iridoid glycosides: 0.2–0.4% agnuside (Abel, 1999); and 0.3% aucubin (Newall et al., 1996). Note: For optimal yield of isoorientin, agnuside, and casticin in extraction, tincture maceration with a drug-to-extract ratio of 1:5 (w/v) in 52% ethanol (v/v) is most effective and will also extract a significant amount of the diterpenes (Meier, 1999).

Pharmacological Actions

Human

Hormonal modulator (BHP, 1996). Early research suggested that chaste tree acts centrally, at the pituitary level, to inhibit release of follicle-stimulating hormone (FSH) and promote the release of luteinizing hormone (LH) (Boon and Smith, 1999; Weiss and Fintelmann, 2000). This action, referred to as a “corpus luteum hormone effect” (Weiss, 1988), was previously thought to lead to an increase in progesterone levels and a corresponding reduction in estrogen levels (Boon and Smith, 1999; Weiss, 1988). However, more recent research indicates that chaste tree appears to exert its medicinal actions through the reduction of prolactin secretion by the pituitary gland (Upton, 2001; Boon and Smith, 1999; Winterhoff, 1998; Newall et al., 1996), through a mechanism involving dopamine antagonism.

Animal

Chaste tree significantly inhibits the stress-induced secretion of prolactin in male rats via its activity on the pituitary gland (Jarry et al., 1991; Winterhoff, 1993; Wuttke et al., 1995). In healthy lactating rats, high doses of chaste tree significantly reduced milk production compared to controls (Winterhoff, 1993, 1998).

In vitro

Chaste tree extract displaces ligands of human opioid-receptor-binding (Brugisser et al., 1999), inhibits prolactin release from rat pituitary cells and exerts a dopamine-agonistic effect through direct dopamine receptor-binding (Jarry et al., 1994; Sluitz et al., 1993; Winterhoff, 1993; Wuttke et al, 1995). It does not appear to modulate rat pituitary cell production of FSH or LH (Jarry et al., 1994) or inhibit spontaneous activity of the isolated rat uterus (Lal et al., 1985). It has antimicrobial activity (Pepeljnjak, et al., 1996).

Mechanism of Action

The exact mechanism of action of chaste tree has not been established (Upton, 2001). However, in vitro and in vivo studies have shown a dopaminergic action resulting in a reduction in elevated prolactin levels (Jarry et al., 1994, 1991; Milewicz et al., 1993; Sluitz et al., 1993; Upton, 2001; Winterhoff, 1998; Wuttke et al., 1995) and a cholinergic mechanism of action (Berger et al., 1999). Isolated diterpenoids, rotundifuran, and 6b,7b-diacetoxy-13-hydroxy-labda-8,14-diene have shown dopaminergic activity in studies on receptor-binding (Hoberg et al., 1999). Chaste tree extract inhibit release of FSH, and promote the release of LH (Boon and Smith, 1999; Weiss and Fintelmann, 2000). This action, referred to as a “corpus luteum hormone effect” (Weiss, 1988), leads to an increase in progesterone levels and a corresponding reduction in estrogen levels (Boon and Smith, 1999; Weiss, 1988). Furthermore, new research indicates that chaste tree appears to exert its medicinal actions through the reduction of prolactin secretion from the pituitary gland (Boon and Smith, 1999; Winterhoff, 1998; Newall et al., 1996).

Animal

Healthy male rats have been involved in studies in which plasma levels of prolactin were measured before and after exposure to chaste tree. Post-treatment prolactin levels were significantly reduced in the chaste tree treatment groups compared to control groups, which indicates inhibition of prolactin secretion in vivo (Winterhoff, 1998; Wuttke et al., 1995).

In vitro

Studies using a test system consisting of rat pituitary cultures revealed a dose-dependent decrease in prolactin secretion (Jarry et al., 1994, 1991; Sluitz et al., 1993; Winterhoff, 1998; Wuttke et al., 1995). Since the prolactin inhibitory effects could be blocked by haloperidol, a dopamine receptor antagonist, chaste tree appears to exert its prolactin-lowering action via dopamine agonism (Merz et al., 1996; Winterhoff, 1998).

Contraindications

According to the German Commission E, no contradictions are known (Blumenthal et al., 1998).

Pregnancy and Lactation: Not recommended for use during pregnancy, according to the Commission E (Blumenthal et al., 1998). The corpus luteum hormone effect of chaste tree can adversely effect the fetal sexual development and therefore chaste tree extract should not be taken during pregnancy. However, in cases of progesterone insufficiency, the increase in progesterone levels can prevent miscarriage in the first trimester of pregnancy (McGuffin et al., 1997), but this exceptional indication during pregnancy should be discussed with the healthcare provider prior to use. Progesterone levels should be closely monitored in the early weeks of pregnancy if a decision is made to withdraw chaste tree before four months.

No known restrictions during lactation (McGuffin et al., 1997). There is insufficient information regarding chaste tree’s influence on prolactin levels in lactating women to reliably predict the lactogenic response. Clinical information and traditional use suggest a galactogogue effect, while in vitro and animal studies using a high dosage range suggest an anti-galactogogue effect. Long-term use of chaste tree (more than two weeks) during lactation may lead to disruption of the lactation amenorrhea state and an early return to fertility, which may or may not be desired.

Adverse Effects

Commission E noted occasional occurrence of itching and urticarial exanthemas. If feelings of breast tension, breast swelling, or menstrual disturbances occur, a healthcare provider should be consulted for diagnosis (Blumenthal et al., 1998). Side effects are rare, occurring in 1–2% of all patients treated (Loch et al., 2000), and may include itching, rash, headache, hair loss, fatigue, agitation, dry mouth, tachycardia, nausea, and increased menstrual flow (Anon., 1998; Dittmar and Böhnert, 1992; Loch et al., 1991; Newall, et al., 1996). The usual percentage of side effects reported in clinical trials is 1–2% of subjects, or 246 side effects in 30 studies, with some subjects reporting multiple effects (total subjects=11,506) (Upton, 2001). The most frequent side effects reported were gastrointestinal distress/nausea (75), acne, skin reactions, urticaria (58), cycle changes (24), headache (10). There is one case report of mild ovarian hyperstimulation in a woman who self-prescribed chaste tree (Cahill, et al., 1994).

Drug Interactions

None known. There is evidence of a dopaminergic effect in animals, which suggests a reciprocal weakening effect can occur with ingestion of dopamine-receptor antagonists such as haloperidol and potentially with dopamine-receptor blocking agents, such as metoclopramide, widely used as an antiemetic (Blumenthal et al., 1998). Due to its apparent hormonal activity, chaste tree may interfere with the effectiveness of oral contraceptives and hormone-replacement therapy (McGuffin et al., 1997; Boon and Smith, 1999); however, this speculative interaction has not been substantiated in clinical case reports (Upton, 2001).

American Herbal Products Association (AHPA) Safety Rating

Class 2b: Should not be used during pregnancy (McGuffin et al., 1997).

Class 2d: May counteract the effectiveness of birth control pills (McGuffin et al., 1997). However, a subsequent in-depth review of chaste tree pharmacology and clinical trials by a co-editor of the AHPA rating writes that this precaution “lacks substantiation” (Upton, 2001).

Regulatory Status

Canada: 32 chaste tree-containing homeopathic drugs have marketing authorization with Drug Identification Numbers (DIN) assigned (Health Canada, 2001). No chaste tree-containing Traditional Herbal Medicines (THM) are presently authorized, though there are no known restrictions.

France: Chaste tree fruit for homeopathic preparations is official in the Pharmacopée Française (Ph.Fr. X, 1989).

Germany: Approved nonprescription drug by the Commission E (Blumenthal et al., 1998). Dried ripe fruit, containing no less than 0.4% (v/w) volatile oil, for preparation of mother tincture and liquid dilutions is official in the German Homeopathic Pharmacopoeia (GHP, 1993). Chaste tree is the subject of a botanical monograph in development for the DAB by the German pharmacopeial commission (Meier, 1999).

Italy: No monograph in the Italian Pharmacopoeia (Meier, 1999).

Sweden: Classified as a drug which must be registered as a pharmaceutical specialty (De Smet et al., 1993). No chaste tree-containing products are presently registered in the Medical Products Agency’s (MPA) “Authorised Natural Remedies” (MPA, 2001a), but chaste tree homeopathic drugs in tablets (D6, D12, and D30) have been registered (MPA, 2001b).

Switzerland: Category D nonprescription drug with sale limited to pharmacies and drugstores (Meier and Hoberg, 1999; Morant and Ruppanner, 2001). Two chaste tree phytomedicines and two chaste tree-containing homeopathic drugs are listed in the Swiss Codex 2000/01 (Ruppanner and Schaefer, 2000). Chaste tree is the subject of a botanical monograph in development by the Swiss pharmacopeial commission (Meier, 1999).

U.K.: Herbal medicine on General Sale List (GSL), Table A (internal or external use), Schedule 1 (requires full Product License) (GSL, 1994). No monograph in the British Pharmacopoeia (Meier, 1999), but one is found in British Herbal Pharmacopoeia.

U.S.: Dietary supplement (USC, 1994). Tincture of the dried or fresh berries, 1:10 (w/v) in 65% alcohol (v/v), is official in the Homeopathic Pharmacopoeia of the United States (HPUS, 1989). No monograph in the USP-NF.

Clinical Review

Eighteen studies are outlined in the table, “Clinical Studies on Chaste Tree,” including 8,336 participants. All of these studies demonstrate positive effects for indications including corpus luteum abnormalities, menstrual cycle abnormalities, and PMS. Most of the studies are open, uncontrolled studies. One double-blind, placebo-controlled (DB, PC) study investigated a native dry extract of chaste tree in the treatment of luteal phase defects due to hyperprolactinemia (Milewicz et al., 1993). Two other studies investigated native dry extracts in the treatment of PMS (Lauritzen et al., 1997; Turner and Mills, 1993). A randomized, DB, PC, parallel study on a commercial chaste tree preparation (Ze440) on 170 women with PMS concluded that the fruit extract is safe and effective in reducing PMS symptoms (Schellenberger et al., 2001). Another recent, multi-center trial on the efficacy of a chaste tree extract (Ze440) investigated 50 patients with PMS, concluding that PMS can be treated successfully as indicated by clear improvement in the main-effect parameter during treatment and the gradual return of that symptom after cessation of treatment. The main effect of treatment seems related to symptomatic relief rather than to the duration of the syndrome (Berger et al., 2000). From 1943 to 1997, approximately 32 clinical studies were conducted on a proprietary chaste berry product (Agnolyt^®, Madaus, Germany). Eight studies were on the product’s effect on PMS, 4 on mastitis and fibrocystic disease, 3 on menopausal symptoms, 3 on increasing lactation, 4 on hyperprolactinemia, 7 on uterine bleeding disorders, 3 on acne, and 4 on miscellaneous menstrual irregularities.

Branded Products*

Agnolyt^® Capsules: Madaus AG / Ostermerheimer Strasse 198 / Köln / Germany / Tel: +49-22-18-9984-76 / Fax: +49-22-18-9987-21 / Email: b.lindener@madaus.de. Chaste tree fruit, hydro-alcoholic, native dry extract 9.58–11.5:1 (w/w), 60% ethanol volume. This product is no longer available.

Agnolyt^® Solution: Madaus AG Chaste tree fruit tincture, ethanol 68% volume. Each 100 g of aqueous-alcoholic solution contains 9 g of a 1:5 tincture.

Alyt^® Solution: Ciba-Geigy AG / Contact: Novartis Consumer Health AG / Route de l’Etraz / CH 1260 Nyon 1 / Switzerland / www.consumer-health.novartis.com. Chaste tree fruit tincture, ethanol 68% volume. Each 100 g of aqueous-alcoholic solution contains 9 g of a 1:5 tincture. Unable to verify manufacturer and availability.

BNO 1095 capsules (Bionorica Agnus castus extract), Bionorica AG / P.O. Box 1851 / D-92308 Neumarkt / Germany / Tel: +49(0)9181-231-90 / Email: international@bionorica.de / www.bionorica.de. Capsules contain 40 mg BP1095E1 [6–12:1 extract (spissum) (70% ethanol)]. This product is not distributed; Bionorica does distribute a tablet product containing BP1095 extract (6–12:1) equivalent to 40 mg crude drug.

Femicur^® N Kapseln: Schaper & Brümmer GmbH & Co. KG/ Bahnhofstrasse 35 / 38259 Salzgitter / Ringelheim / Germany / Tel: +49-5341-30-70 / Fax: +49-5341-30-71-24 / Email: info@schaperbruemmer.de / www.schaper-bruemmer.com. 1 capsule contains dry extract of fruits of Vitex agnus-castus (7–13:1) 4 mg, extractant: ethanol 60% (m/m).

PreMens^® Ze440: Zeller AG / Seeblickstrasse 4 / CH-8590 Romanshorn 1 / Switzerland / www.zellerag.ch. One coated tablet contains 40 mg chaste tree fruit hydro-alcoholic extract of which 20 mg is native dry extract, 6.0–12.0:1 (w/w) and 20 mg is lactose as excipient, 60% ethanol by weight. Normalized to contain a minimum of 0.6% casticin.

Strotan^® Kapseln: Strathmann AG & Co. / Sellhopsweg 1 / 22459 Hamburg / Germany / Tel: +49-40-55-9050 / Fax: +49-40-55-9051-00 / Email: info@strathmann.de / www.strathmann.de. Soft-gel capsule contains 20 mg chaste tree fruit, hydro-alcoholic (50–70% v/v), native dry extract. Chemically defined constituents include the iridoids aucubin and agnuside, flavonoids, essential and fatty oils, and the bitter principle castin.

*American equivalents are found in the Product Table beginning on page 398.

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